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Nanoparticle-exposure-triggered virus reactivation induces lung emphysema in mice.
ACS Nano 17, 21056-21072 (2023)
Nanoparticles (NPs) released from engineered materials or combustion processes as well as persistent herpesvirus infection are omnipresent and are associated with chronic lung diseases. Previously, we showed that pulmonary exposure of a single dose of soot-like carbonaceous NPs (CNPs) or fiber-shaped double-walled carbon nanotubes (DWCNTs) induced an increase of lytic virus protein expression in mouse lungs latently infected with murine γ-herpesvirus 68 (MHV-68), with a similar pattern to acute infection suggesting virus reactivation. Here we investigate the effects of a more relevant repeated NP exposure on lung disease development as well as herpesvirus reactivation mechanistically and suggest an avenue for therapeutic prevention. In the MHV-68 mouse model, progressive lung inflammation and emphysema-like injury were detected 1 week after repetitive CNP and DWCNT exposure. NPs reactivated the latent herpesvirus mainly in CD11b+ macrophages in the lungs. In vitro, in persistently MHV-68 infected bone marrow-derived macrophages, ERK1/2, JNK, and p38 MAPK were rapidly activated after CNP and DWCNT exposure, followed by viral gene expression and increased viral titer but without generating a pro-inflammatory signature. Pharmacological inhibition of p38 activation abrogated CNP- but not DWCNT-triggered virus reactivation in vitro, and inhibitor pretreatment of latently infected mice attenuated CNP-exposure-induced pulmonary MHV-68 reactivation. Our findings suggest a crucial contribution of particle-exposure-triggered herpesvirus reactivation for nanomaterial exposure or air pollution related lung emphysema development, and pharmacological p38 inhibition might serve as a protective target to alleviate air pollution related chronic lung disease exacerbations. Because of the required precondition of latent infection described here, the use of single hit models might have severe limitations when assessing the respiratory toxicity of nanoparticle exposure.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Emphysema ; Nanoparticles ; P38 Mapk ; Virus Reactivation ; γ-herpesvirus; Activated Protein-kinase; Sarcoma-associated Herpesvirus; Walled-carbon-nanotubes; Long-term Exposure; Inflammatory Response; Pulmonary-fibrosis; Air-pollution; Bone-marrow; Infection; Cells
ISSN (print) / ISBN
1936-0851
e-ISSN
1936-086X
Journal
ACS Nano
Quellenangaben
Volume: 17,
Issue: 21,
Pages: 21056-21072
Publisher
American Chemical Society (ACS)
Publishing Place
1155 16th St, Nw, Washington, Dc 20036 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Lung Health and Immunity (LHI)
Institute of Asthma and Allergy Prevention (IAP)
Institute of Experimental Genetics (IEG)
Research Unit Analytical Pathology (AAP)
Institute of Lung Biology (LHI)
Institute of Asthma and Allergy Prevention (IAP)
Institute of Experimental Genetics (IEG)
Research Unit Analytical Pathology (AAP)
Institute of Lung Biology (LHI)
Grants
China Scholarship Council (CSC)
European Union (EU)
German Center for Lung Research (DZL)
European Union (EU)
German Center for Lung Research (DZL)